Abstract
Functional imaging studies consistently report abnormal amygdala activity in major depressive disorder (MDD). Neuroanatomical correlates are less clear: imaging studies have produced mixed results on amygdala volume, and postmortem neuroanatomic studies have only examined cell densities in portions of the amygdala or its subregions in MDD. Here, we present a stereological analysis of the volume of, and the total number of, neurons, glia, and neurovascular (pericyte and endothelial) cells in the basolateral amygdala in MDD. Postmortem tissues from 13 subjects with MDD and 10 controls were examined. Sections (~15/subject) taken throughout the rostral–caudal extent of the basolateral amygdala (BLA) were stained for Nissl substance and utilized for stereological estimation of volume and cell numbers. Results indicate that depressed subjects had a larger lateral nucleus than controls and a greater number of total BLA neurovascular cells than controls. There were no differences in the number or density of neurons or glia between depressed and control subjects. These findings present a more detailed picture of BLA cellular anatomy in depression than has previously been available. Further studies are needed to determine whether the greater number of neurovascular cells in depressed subjects may be related to increased amygdala activity in depression.
This is a preview of subscription content, access via your institution.




References
Abitz M, Nielsen RD, Jones EG, Laursen H, Graem N, Pakkenberg B (2007) Excess of neurons in the human newborn mediodorsal thalamus compared with that of the adult. Cereb Cortex 17:2573–2578
Almeida JR, Versace A, Mechelli A, Hassel S, Quevedo K, Kupfer DJ, Phillips ML (2009) Abnormal amygdala-prefrontal effective connectivity to happy faces differentiates bipolar from major depression. Biol Psychiatry 66:451–459
Almeida OP, Ford AH, Flicker L, Hankey GJ, Yeap BB, Clancy P, Golledge G (2014) Angiogenesis inhibition and depression in older men. J Psychiatry Neurosci 39:200–205
Altshuler LL, Abulseoud OA, Foland-Ross L, Bartzokis G, Chang S, Mintz J, Hellemann G, Vinters HV (2010) Amygdala astrocyte reduction in subjects with major depressive disorder but not bipolar disorder. Bipolar Disord 12:541–549
Anand A, Li Y, Wang Y, Wu J, Gao S, Bukhari L, Mathews VP, Kainin A, Lowe MJ (2005) Activity and connectivity of brain mood regulating circuit in depression: a functional magnetic resonance study. Biol Psychiatry 57:1079–1088
Anisman H, Du L, Palkovits M, Faludi G, Kovacs GG, Szontagh-Kishazi P, Merali Z, Poulter MO (2008) Serotonin receptor subtype and p11 mRNA expression in stress-relevant brain regions of suicide and control subjects. J Psychiatry Neurosci 33:131–141
Armulik A, Genové G, Nisancioglu MH, Wallgard E, Niaudet C, He L, Norlin J, Lindblom P, Strittmatter K, Johansson BR, Betsholtz C (2010) Pericytes regulate the blood-brain barrier. Nature 468:557–561
Ashtari M, Avants B, Cyckowski L, Cervellione KL, Roofeh D, Cook P, Gee J, Sevy S, Kumra S (2011) Medial temporal structures and memory functions in adolescents with heavy cannabis use. J Psychiatr Res 45:1055–1066
Baumann B, Danos P, Diekmann S, Krell D, Bielau H, Geretsegger C, Wurthmann C, Bernstein HG, Bogerts B (1999) Tyrosine hydroxylase immunoreactivity in the locus coeruleus is reduced in depressed non-suicidal patients but normal in depressed suicide patients. Eur Arch Psychiatry Clin Neurosci 249:212–219
Bell RD, Winkler EA, Sagare AP, Singh I, LaRue B, Deane R, Zlokovic BV (2010) Pericytes control key neurovascular functions and neuronal phenotype in the adult brain and during brain aging. Neuron 68:409–427
Bergers G, Song S (2005) The role of pericytes in blood-vessel formation and maintenance. Neuro Oncol 7:452–464
Berretta S, Pantazopoulos H, Lange N (2007) Neuron numbers and volume of the amygdala in subjects diagnosed with bipolar disorder or schizophrenia. Bio Psychiatry 62:884–893
Bezchlibnyk YB, Sun X, Wang JF, MacQueen GM, McEwen BS, Young LT (2007) Neuron somal size is decreased in the lateral amygdalar nucleus of subjects with bipolar disorder. J Psychiatry Neurosci 32:203–210
Boldrini M, Hen R, Underwood MD, Rosoklija GB, Dwork AJ, Mann JJ, Arango V (2012) Hippocampal angiogenesis and progenitor cell proliferation are increased with antidepressant use in major depression. Biol Psychiatry 72:562–571
Bowley MP, Drevets WC, Ongür D, Price JL (2002) Low glial numbers in the amygdala in major depressive disorder. Biol Psychiatry 52:404–412
Braendgaard H, Gundersen HJ (1986) The impact of recent stereological advances on quantitative studies of the nervous system. J Neurosci Methods 18:39–78
Brüne M, Schöbel A, Karau R, Faustmann PM, Dermietzel R, Juckel G, Petrasch-Parwez E (2011) Neuroanatomical correlates of suicide in psychosis: the possible role of von Economo neurons. PLoS One 6:e20936. doi:10.1371/journal.pone.0020936
Carlsen J, Heimer L (1988) The basolateral amygdaloid complex as a cortical-like structure. Brain Res 441:377–380
Carlson PJ, Singh JB, Zarate CA Jr, Drevets WC, Manji HK (2006) Neural circuitry and neuroplasticity in mood disorders: insights for novel therapeutic targets. NeuroRx 3:22–41
Christensen JR, Larsen KB, Lisanby SH, Scalia J, Arango V, Dwork AJ, Pakkenberg B (2007) Neocortical and hippocampal neuron and glial cell numbers in the rhesus monkey. Anat Rec 290:330–340
Cousijn J, Wiers RW, Ridderinkhof KR, van den Brink W, Veltman DJ, Goudriaan AE (2012) Grey matter alterations associated with cannabis use: results of a VBM study in heavy cannabis users and healthy controls. Neuroimage 59:3845–3851
deCampo DM, Fudge JL (2012) Where and what is the paralaminar nucleus? A review on a unique and frequently overlooked area of the primate amygdala. Neurosci Biobehav Rev 36:520–535
Dorph-Petersen KA, Nyengaard JR, Gundersen HJ (2001) Tissue shrinkage and unbiased stereological estimation of particle number and size. J Microsc 204:232–246
Drevets WC, Price JL, Bardgett ME, Reich T, Todd RD, Raichle ME (2002) Glucose metabolism in the amygdala in depression: relationship to diagnostic subtype and plasma cortisol levels. Pharmacol Biochem Behav 71:431–447
Drevets WC, Price JL, Furey ML (2008) Brain structural and functional abnormalities in mood disorders: implications for neurocircuitry models of depression. Brain Struct Funct 213:93–118
Frodl T, Meisenzahl EM, Zetzsche T, Bottlender R, Born C, Groll C, Jäger M, Leinsinger G, Hahn K, Möller HJ (2002) Enlargement of the amygdala in patients with a first episode of major depression. Biol Psychiatry 51:708–714
Frodl T, Meisenzahl EM, Zetzsche T, Born C, Jäger M, Groll C, Bottlender R, Leinsinger G, Möller HJ (2003) Larger amygdala volumes in first depressive episode as compared to recurrent major depression and healthy control subjects. Biol Psychiatry 53:338–344
Galea LA, Urban KA, Epp JR, Brummelte S, Barha CK, Wilson WL, Lieblich SE, Pawluski JL (2008) Endocrine regulation of cognition and neuroplasticity: our pursuit to unveil the complex interaction between hormones, the brain, and behaviour. Can J Exp Psychol 62:247–260
Gardella D, Hatton WJ, Rind HB, Rosen GD, von Bartheld CS (2003) Differential tissue shrinkage and compression in the z-axis: implications for optical disector counting in vibratome-, plastic- and cryosections. J Neurosci Methods 124:45–59
Gerhardt H, Betsholtz C (2003) Endothelial-pericyte interactions in angiogenesis. Cell Tissue Res 314:15–23
Girouard H, Iadecola C (2006) Neurovascular coupling in the normal brain and in hypertension, stroke, and Alzheimer’s disease. J Appl Physiol 100:328–335
Gloor P (1997) The temporal lobe and limbic system. Oxford University Press, New York
Gos T, Krell D, Bielau H, Brisch R, Trübner K, Steiner J, Bernstein HG, Jankowski Z, Bogerts B (2008) Tyrosine hydroxylase immunoreactivity in the locus coeruleus is elevated in violent suicidal depressed patients. Eur Arch Psychiatry Clin Neurosci 258:513–520
Gundersen HJ, Jensen EB (1987) The efficiency of systematic sampling in stereology and its prediction. J Microsc 147:229–263
Gundersen HJ, Bendtsen TF, Korbo L, Marcussen N, Møller A, Nielsen K, Nyengaard JR, Pakkenberg B, Sørensen FB, Vesterby A, West MJ (1988) Some new, simple and efficient stereological methods and their use in pathological research and diagnosis. APMIS 96:379–394
Gundersen HJ, Jensen EB, Kiêu K, Nielsen J (1999) The efficiency of systematic sampling in stereology–reconsidered. J Microsc 193:199–211
Hamidi M, Drevets WC, Price JL (2004) Glial reduction in amygdala in major depressive disorder is due to oligodendrocytes. Biol Psychiatry 55:563–569
Hamilton JP, Siemer M, Gotlib IH (2008) Amygdala volume in major depressive disorder: a meta-analysis of magnetic resonance imaging studies. Mol Psychiatry 13:993–1000
Hastings RS, Parsey RV, Oquendo MA, Arango V, Mann JJ (2004) Volumetric analysis of the prefrontal cortex, amygdala, and hippocampus in major depression. Neuropsychopharmacology 29:952–959
He F, Sun YE (2007) Glial cells more than support cells? Int J Biochem Cell Biol 39:661–665
Hercher C, Parent M, Flores C, Canetti L, Turecki G, Mechawar N (2009) Alcohol dependence-related increase of glial cell density in the anterior cingulate cortex of suicide completers. J Psychiatry Neurosci 34:281–288
Inagaki M, Matsuoka Y, Sugahara Y, Nakano T, Akechi T, Fujimori M, Imoto S, Murakami K, Uchitomi Y (2004) Hippocampal volume and first major depressive disorder after cancer diagnosis in breast cancer survivors. Am J Psychiatry 161:2263–2270
Jansson L, Hellsten J, Tingström A (2006) Region specific hypothalamic neuronal activation and endothelial cell proliferation in response to electroconvulsive seizures. Biol Psychiatry 60:874–881
Juraska JM, Rubinow MJ (2008) Hormones and memory. In: Byrne J, Eichenbaum H (eds) Learning and memory: a comprehensive reference, vol 3., Memory systemsElsevier, London, pp 503–520
Kalaria RN (1996) Cerebral vessels in ageing and Alzheimer’s disease. Pharmacol Ther 72:193–214
Karolewicz B, Szebeni K, Gilmore T, Maciag D, Stockmeier CA, Ordway GA (2009) Elevated levels of NR2A and PSD-95 in the lateral amygdala in depression. Int J Neuropsychopharmacol 12:143–153
Klimek V, Schenck JE, Han H, Stockmeier CA, Ordway GA (2002) Dopaminergic abnormalities in amygdaloid nuclei in major depression: a postmortem study. Biol Psychiatry 52:740–748
Kreczmanski P, Heinsen H, Mantua V, Woltersdorf F, Masson T, Ulfig N, Schmidt-Kastner R, Korr H, Steinbusch HW, Hof PR, Schmitz C (2007) Volume, neuron density and total neuron number in five subcortical regions in schizophrenia. Brain 130:678–692
Kronenberg G, Tebartz van Elst L, Regen F, Deuschle M, Heuser I, Colla M (2009) Reduced amygdala volume in newly admitted psychiatric in-patients with unipolar major depression. J Psychiatr Res 43:1112–1117
Lakshminarasimhan H, Chattarji S (2012) Stress leads to contrasting effects on the levels of brain derived neurotrophic factor in the hippocampus and amygdala. PLoS One 7:e30481. doi:10.1371/journal.pone.0030481
Lange C, Irle E (2004) Enlarged amygdala volume and reduced hippocampal volume in young women with major depression. Psychol Med 34:1059–1064
MacMaster FP, Mirza Y, Szeszko PR, Kmiecik LE, Easter PC, Taormina SP, Lynch M, Rose M, Moore GJ, Rosenberg DR (2008) Amygdala and hippocampal volumes in familial early onset major depressive disorder. Biol Psychiatry 63:385–390
Malykhin NV, Carter R, Hegadoren KM, Seres P, Coupland NJ (2012) Fronto-limbic volumetric changes in major depressive disorder. J Affect Disord 136:1104–1113
Matthews PR, Harrison PJ (2012) A morphometric, immunohistochemical, and in situ hybridization study of the dorsal raphe nucleus in major depression, bipolar disorder, schizophrenia, and suicide. J Affect Disord 137:125–134
Matthews SC, Strigo IA, Simmons AN, Yang TT, Paulus MP (2008) Decreased functional coupling of the amygdala and supragenual cingulate is related to increased depression in unmedicated individuals with current major depressive disorder. J Affect Disord 111:13–20
McDonald AJ (1998) Cortical pathways to the mammalian amygdala. Prog Neurobiol 55:257–332
Miguel-Hidalgo JJ, Rajkowska G (1999) Immunohistochemistry of neural markers for the study of the laminar architecture in celloidin sections from the human cerebral cortex. J Neurosci Methods 93:69–79
Monkul ES, Hatch JP, Nicoletti MA, Spence S, Brambilla P, Lacerda AL, Sassi RB, Mallinger AG, Keshavan MS, Soares JC (2007) Fronto-limbic brain structures in suicidal and non-suicidal female patients with major depressive disorder. Mol Psychiatry 12:360–366
Moore CI, Cao R (2008) The hemo-neural hypothesis: on the role of blood flow in information processing. J Neurophysiol 99:2035–2047
Mouton P (2002) Principles and practices of unbiased stereology. Johns Hopkins University Press, Baltimore
Munn MA, Alexopoulos J, Nishino T, Babb CM, Flake LA, Singer T, Ratnanather JT, Huang H, Todd RD, Miller MI, Botteron KN (2007) Amygdala volume analysis in female twins with major depression. Biol Psychiatry 62:415–422
Rajkowska G, Goldman-Rakic PS (1995) Cytoarchitectonic definition of prefrontal areas in the normal human cortex: I. Remapping of areas 9 and 46 using quantitative criteria. Cereb Cortex 5:307–322
Rotheneichner P, Lange S, O’Sullivan A, Marschallinger J, Zaunmair P, Geretsegger C, Aigner L, Couillard-Despres S (2014) Hippocampal neurogenesis and antidepressive therapy: shocking relations. Neural Plast. doi:10.1155/2014/723915
Savitz JB, Drevets WC (2009) Imaging phenotypes of major depressive disorder: genetic correlates. Neuroscience 164:300–330
Schumann CM, Amaral DG (2005) Stereological estimation of the number of neurons in the human amygdaloid complex. J Comp Neurol 491:320–329
Schumann CM, Amaral DG (2006) Stereological analysis of amygdala neuron number in autism. J Neurosci 26:7674–7679
Sengillo JD, Winkler EA, Walker CT, Sullivan JS, Johnson M, Zlokovic BV (2013) Deficiency in mural vascular cells coincides with blood-brain barrier disruption in Alzheimer’s disease. Brain Pathol 23:303–310
Sheline YI, Gado MH, Price JL (1998) Amygdala core nuclei volumes are decreased in recurrent major depression. NeuroReport 9:2023–2028
Sibille E, Wang Y, Joeyen-Waldorf J, Gaiteri C, Surget A, Oh S, Belzung C, Tseng GC, Lewis DA (2009) A molecular signature of depression in the amygdala. Am J Psychiatry 166:1011–1024
Siegle GJ, Konecky RO, Thase ME, Carter CS (2003) Relationships between amygdala volume and activity during emotional information processing tasks in depressed and never-depressed individuals. Ann N Y Acad Sci 985:481–484
Spoletini I, Piras F, Fagioli S, Rubino IA, Martinotti G, Siracusano A, Caltagirone C, Spalletta G (2011) Suicidal attempts and increased right amygdala volume in schizophrenia. Schizophrenia Res 125:30–40
Steiner J, Bielau H, Brisch R, Danos P, Ullrich O, Mawrin C, Bernstein HG, Bogerts B (2008) Immunological aspects in the neurobiology of suicide: elevated microglial density in schizophrenia and depression is associated with suicide. J Psychiatr Res 42:151–157
Stockmeier CA, Mahajan GJ, Konick LC, Overholser JC, Jurjus GJ, Meltzer HY, Uylings HB, Friedman L, Rajkowska G (2004) Cellular changes in the postmortem hippocampus in major depression. Biol Psychiatry 56:640–650
Tang Y, Wang F, Xie G, Liu J, Li L, Su L, Liu Y, Hu X, He Z, Blumberg HP (2007) Reduced ventral anterior cingulate and amygdala volumes in medication-naïve females with major depressive disorder: a voxel-based morphometric magnetic resonance imaging study. Psychiatry Res 156:83–86
Ullian EM, Sapperstein SK, Christopherson KS, Barres BA (2001) Control of synapse number by glia. Science 291:657–661
Underwood MD, Khaibulina AA, Ellis SP, Moran A, Rice PM, Mann JJ, Arango V (1999) Morphometry of the dorsal raphe nucleus serotonergic neurons in suicide victims. Biol Psychiatry 46:473–483
Uylings HB, van Eden CG, Hofman MA (1986) Morphometry of size/volume variables and comparison of their bivariate relations in the nervous system under different conditions. J Neurosci Methods 18:19–37
van Eijndhoven P, van Wingen G, van Oijen K, Rijpkema M, Goraj B, Jan Verkes R, Oude Voshaar R, Fernández G, Buitelaar J, Tendolkar I (2009) Amygdala volume marks the acute state in the early course of depression. Biol Psychiatry 65:812–818
Vassilopoulou K, Papathanasiou M, Michopoulos I, Boufidou F, Oulis P, Kelekis N, Rizos E, Nikolaou C, Pantelis C, Velakoulis D, Lykouras L (2013) A magnetic resonance imaging study of hippocampal, amygdala and subgenual prefrontal cortex volumes in major depression subtypes: melancholic versus psychotic depression. J Affect Disord 146:197–204
von Gunten A, Fox NC, Cipolotti L, Ron MA (2000) A volumetric study of hippocampus and amygdala in depressed patients with subjective memory problems. J Neuropsychiatry Clin Neurosci 12:493–498
Vyas A, Mitra R, Shankaranayana Rao BS, Chattarji S (2002) Chronic stress induces contrasting patterns of dendritic remodeling in hippocampal and amygdaloid neurons. J Neurosci 22:6810–6818
Vyas A, Jadhav S, Chattarji S (2006) Prolonged behavioral stress enhances synaptic connectivity in the basolateral amygdala. Neuroscience 143:387–393
Weniger G, Lange C, Irle E (2006) Abnormal size of the amygdala predicts impaired emotional memory in major depressive disorder. J Affect Disord 94:219–229
West MJ, Slomianka L, Gundersen HJ (1991) Unbiased stereological estimation of the total number of neurons in the subdivisions of the rat hippocampus using the optical fractionator. Anat Rec 231:482–497
Winkler EA, Sengillo JD, Sullivan JS, Henkel JS, Appel SH, Zlokovic BV (2013) Blood-spinal cord barrier breakdown and pericyte reductions in amyotrophic lateral sclerosis. Acta Neuropathol 125:111–120
Xiang L, Szebeni K, Szebeni A, Klimek V, Stockmeier CA, Karolewicz B, Kalbfleisch J, Ordway GA (2008) Dopamine receptor gene expression in human amygdaloid nuclei: elevated D4 receptor mRNA in major depression. Brain Res 1207:214–224
Yoshikawa E, Matsuoka Y, Yamasue H, Inagaki M, Nakano T, Akechi T, Kobayakawa M, Fujimori M, Nakaya N, Azizuki N, Imoto S, Murakami K, Kasai K, Uchitomi Y (2006) Prefrontal cortex and amygdala volume in first minor or major depressive episode after cancer diagnosis. Biol Psychiatry 59:707–712
Zetzsche T, Preuss UW, Bondy B, Frodl T, Zill P, Schmitt G, Koutsouleris N, Rujescu D, Born C, Reiser M, Möller HJ, Meisenzahl EM (2008) 5-HT1A receptor gene C-1019 G polymorphism and amygdala volume in borderline personality disorder. Genes Brain Behav 7:306–313
Acknowledgments
We acknowledge the invaluable contributions made by the families consenting to donate brain tissue and be interviewed. We also thank the Cuyahoga County Coroner’s Office and staff, Cleveland, Ohio, for their willing assistance. For some of the subjects, the services of Timothy M. De Jong and Lisa Larkin in acquiring written consent and tissue collection, respectively, are gratefully acknowledged. This study was supported by Public Health Service Grant Nos. P30 GM103328 (CAS), MH67996 (CAS), and MH054846 (DCS), and a postdoctoral grant from the Hearin Foundation (MJR). Funding sources had no other role in the study design or in the analysis or interpretation of data.
Conflict of interest
The authors have no conflicts of interest to declare.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Rubinow, M.J., Mahajan, G., May, W. et al. Basolateral amygdala volume and cell numbers in major depressive disorder: a postmortem stereological study. Brain Struct Funct 221, 171–184 (2016). https://doi.org/10.1007/s00429-014-0900-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00429-014-0900-z